It has been conventionally known that arachidonic acid metabolites, prostaglandin E.sub.2 (PGE.sub.2), prostaglandin I.sub.2 (PGI.sub.2) and thromboxane B.sub.2 (TXB.sub.2) are deeply involved in inflammations. An important enzyme in this arachidonic acid metabolism is cyclooxygenase. Cyclooxygenase is a synthase which produces prostaglandin H.sub.2 (PGH.sub.2) from arachidonic acid via prostaglandin G.sub.2 (PGG.sub.2), and includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
With respect to COX-1, cDNA cloning was performed in 1988 and its primary structure and induction by various factors have been clarified [Yokoyama, C. et al.: Biochem. Biophys. Res. Commun., 165: 888-894 (1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083: 1-17 (1991); DeWitt, D. L.: Biochim. Biophys. Acta, 1083: 121-134 (1991)]. On the other hand, the existence of an isozyme of COX-1, namely, COX-2, was suggested in 1989 [Holtzman, M. J. et al.: J. Biol. Chem., 267: 21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and human have been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA, 88: 2692-2696 (1991); Kujubu, D. A. et al.: J. Biol. Chem., 266: 12866-12872 (1991); Hla, T. et al.: Proc. Natl. Acad. Sci. USA, 89: 7384-7388 (1992)]. COX-2 is quickly induced by phorbol ester, lipopolysaccharide (LPS) and the like, and the relationship with inflammation and bronchial asthma has been inferred.
COX-1 systemically and constantly exists in almost all cells and is physiologically concerned with the generation of prostaglandin (PG) necessary for the functions of, for example, stomach and kidney. Therefore, when COX-1 is inhibited, the biosynthesis of PG by vasodilative PGE.sub.2 and PGI.sub.2, which protect gastric mucosa, is suppressed, and the protective action on the gastric mucosa becomes degraded, as a result of which ulcer is caused. With regard to a symptom associated with a decrease in renal blood flow, in general terms, the renal blood flow can be increased by promoting the production of vasodilative PGE.sub.2 in the body, thereby to appropriately maintain glomerular filtration rate. However, if the production of such vasodilative PG is suppressed due to the inhibition of COX-1, the renal blood flow becomes less, so that a side-effect such as the onset of ischemic acute renal insufficiency is sometimes caused.
On the other hand, COX-2 exists in particular sites such as monocytes, synovial cells, granulosa cells and intravenous endothelial cells, and is topically expressed when inflammation is caused. It is therefore considered that PG generated by COX-2 is deeply concerned with inflammation and tissue disorders.
Currently, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen and naproxen have been widely used in clinical situations. Most of these NSAIDs are anti-inflammatory drugs which selectively inhibit cyclooxygenase (COX) and are associated with side-effects such as disorders in the digestive tract. Such side-effects are considered to be caused by the fact that they, though certainly selectively inhibit COX, inhibit both COX-1 and COX-2.
It follows therefrom that selective inhibition, without inhibition of COX-1, of solely COX-2 which is specifically induced at the inflammatory sites, would enable provision of a superior anti-inflammatory drug free of side-effects such as disorders in the digestive tract (e.g., ulcer).
There are various reports on anti-inflammatory drugs having selective COX-2 inhibitory activity, which aim at reducing side-effects such as disorders in the digestive tract.
For example, WO94/15932 discloses, as COX-2 inhibitors, 5-membered heterocyclic compounds substituted by bisaryl, such as thiophene, furan and pyrrole, which are specifically exemplified by 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However, this publication merely shows a 5-membered heterocyclic compound such as thiophene having aryl or heteroaryl at the 3-position or 4-position.
Moreover, various reports deal with anti-inflammatory drugs having cyclooxygenase-inhibitory action, prostaglandin synthesis-inhibitory action or thromboxane A.sub.2 synthesis-inhibitory action.
For example, U.S. Pat. No. 5,134,142 discloses pyrazole derivatives such as ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate; U.S. Pat. No. 4,457,171 discloses thiazole derivatives such as 2-methylthio-5-phenyl-4-(3-pyridyl)-thiazole; and U.S. Pat. No. 4,612,321 discloses thiazole derivatives such as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. These publications mention that they are useful as anti-inflammatory drugs, whereas they do not disclose if they have selective inhibitory action on COX-2 to reduce side-effects, or any suggestion of it.
There are other reports on the following heterocyclic aromatic compounds.
For example, U.S. Pat. No. 4632930 discloses oxazole compounds such as 5-cyclohexyl-4-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluoro-meth yl)oxazole-2-methanol. Yet, the compounds disclosed therein are effective for hypertension and their usefulness as anti-inflammatory drugs or any suggestion to that effect are not included.
Japanese Patent Application under PCT laid-open under Kohyo No. 500054/1984 discloses oxazole derivatives having heteroaryl or carbon ring aryl at the 4-position or 5-position of oxazole ring and having carboxy, ester or amidized carboxy via lower alkylene at the 2-position thereof, such as ethyl 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese Patent Application under PCT laid-open under Kohyo No. 500055/1984 discloses imidazole derivatives having heteroaryl and/or carbon ring aryl at the 4-position or 5-position of imidazole ring and having formyl or acetalized formyl via lower alkylene at the 2-position thereof, such as 2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal. These publications teach that these compounds are effective as dermal antiphlogistic or mucosal antiphlogistic for inflammatory dermal diseases, but do not teach or even suggest that they have selective inhibitory action on COX-2.
Japanese Patent Unexamined Publication No. 70446/1993 discloses N-thiazolylsulfonamide derivatives such as N-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamid e; and Japanese Patent Unexamined Publication No. 83372/1990 discloses cyclohexylimidazole derivatives such as 4-cyclohexyl-5-phenyl-2-t-butyl-imidazole. These publications only exemplify cyclohexyl as a substituent and include no suggestion as to the substitution with phenyl substituted by aminosulfonyl, lower alkylaminosulfonyl or lower alkylsulfonyl.
U.S. Pat. No. 5,380,738 discloses oxazole compounds such as 2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2 inhibitors. However, the compounds described in this publication are mainly characterized by 4-fluorophenyl and 4-methylsulfonylphenyl at the 4-position and 5-position of oxazole ring, and do not suggest the compounds having specific substituents in combination, as in the present invention.
Not only in COX-2 inhibitors but also in the field of anti-inflammatory drugs, preferable phenyl substituent for 5-membered heterocyclic ring skeleton has been conventionally considered to be monosubstituted phenyl such as 4-methylsulfonylphenyl and 4-methoxyphenyl, and di-substituted phenyl has been barely tried (e.g., UK Patent No. 1206403).